Modeling Peptides in Aqueous Ionic Liquid Mixtures: A Quantum Mechanics/Molecular Dynamics Study of Structural and NMR Properties

In this pilot study, structural properties and 1H NMR chemical shifts of an Ala-Glu-Pro-Phe peptide dissolved in an aqueous solution and an aqueous mixture of the 1-ethyl-3-methylimidazolium trifluoroacetate ionic liquid (IL) have been scrutinized using an integrated computational protocol based on classical molecular dynamics (MD) simulations and combined quantum mechanics/molecular mechanics (QM/MM) approaches for NMR shielding constants. Two long-lived trans and cis Pro isomers of the tetrapeptide have been considered. MD simulations as long as 400 ns were found to be too short to ensure complete sampling of the conformational phase space of the peptide in aqueous IL solution, and thus, the analysis was performed for four distinct conformations of either isomer of the peptide separately. Solvent molecules within the first solvation shell of the solute were treated quantum mechanically in the QM/MM calculations of 1H NMR shieldings. The constituent ions of the IL were seen to condense around the tetrapeptide, abundantly displacing water molecules from its first solvation shell, and the preference for the imidazolium cations to condense around the peptide in solution was identified. Prominent hydrogen bonding together with π-π stacking interactions between the benzene ring in the Phe residue and the imidazolium ring of the cations assist in maintaining the ionic cage that surrounds the peptide. Accordingly, the computed 1H NMR signals of the peptide in aqueous IL solution are shifted w.r.t. their values in aqueous solution. The computational results allow identifying several 1H NMR signals which could be potential spectral NMR markers of the conformational or the isomeric state of the tetrapeptide.